 | This article provides insufficient context for those unfamiliar with the subject.(April 2018) |
Type 1 regulatory cells or Tr1 (TR1) cells are a class of regulatory T cells participating in peripheral immunity as a subsets of CD4+ T cells. Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role is to induce and maintain peripheral tolerance [1] and suppress tissue inflammation in autoimmunity and graft vs. host disease. [2]
The specific cell-surface markers for Tr1 cells in humans and mice are CD4+ CD49b+LAG-3+ CD226+ from which LAG-3+ and CD49b+ are indispensable. [3] LAG-3 is a membrane protein on Tr1 cells that negatively regulates TCR-mediated signal transduction in cells. LAG-3 activates dendritic cells (DCs) and enhances the antigen-specific T-cell response which is necessary for Tr1 cells antigen specificity. [3] [4] [5] CD49b belongs to the integrin family and is a receptor for many (extracellular) matrix and non-matrix molecules. CD49b provides only little contribution to the differentiation and function of Tr1 cells. [3]
They characteristically produce high levels of IL-10, IFN-γ, IL-5 and also TGF- β but neither IL-4 nor IL-2. [6] Production of IL-10 is also much more rapid than its production by other T-helper cell types. [6]
Tr1 cells do not constitutively express FOXP3 [7] but only transiently, upon their activation and in smaller amounts than CD25+ FOXP3+ regulatory cells. [8] FOXP3 is not required for Tr1 induction, nor for its function. [1] They also express repressor of GATA-3 (ROG), while CD25+ FOXP3+ regulatory cells do not. [9] ROG then downregulates GATA-3, a characteristic transcription factor for Th2 cells.
Tr1 cells express high levels of regulatory factors, such as glucocorticoid-induced tumor necrosis factor receptor (GITR), OX40 (CD134), and tumor-necrosis factor receptor (TNFRSF9). [8] Resting human Tr1 cells express Th1 associated chemokine receptors CXCR3 and CCR5, and Th2-associated CCR3, CCR4 and CCR8. [8] Upon activation, Tr1 cells migrate preferentially in response to I-309, a ligand for CCR8. [8]
The suppressing and tolerance-inducing effect of Tr1 cells is mediated mainly by cytokines. The other mechanism as cell to cell contact, modulation of dendritic cells, metabolic disruption and cytolysis is however also available to them. [1] In vivo Tr1 cells need to be activated, to be able to exert their regulatory effects. [6]
Tr1 cells secrete large amount of suppressing cytokines IL-10 and TGF-β. [7] IL-10 directly inhibits T cells by blocking its production of IL-2, IFN-γ and GM-CSF and have tolerogenic effect on B cells and support differentiation of other regulatory T cells. [10] IL-10 indirectly downregulates MHC II molecules and co-stimulatory molecules on antigen-presenting cells (APC) and force them to upregulate tolerogenic molecules such as ILT-3, ILT-4 and HLA-G. [11]
Type 1 regulatory T cells poses inhibitory receptor CTLA-4 through which they exert suppressor function. [12]
Tr1 cells can express ectoenzymes CD39 and CD73 and are suspected of generating adenosine which suppresses effector T cell proliferation and their cytokine production in vitro. [13]
Tr1 cells can both express Granzyme A and granzyme B. It was shown recently, that Tr1 cells, in vitro and also ex vivo, specifically lyse cells of myeloid origin, but not other APC or T or B lymphocytes. [14] Cytolysis indirectly suppresses immune response by reducing numbers of myeloid-origin antigen presenting cells.
Tr 1 cells are inducible, arising from precursors naive T cells. They can be differentiated ex vivo and in vivo. [15] The ways of Tr1 cells induction in vivo, ex vivo and in vitro differ and also envelop many different approaches but the molecular mechanism appears to be conserved.
IL-27, together with TGF-β induces IL-10–producing regulatory T cells with Tr1-like properties cells. [16] [17] IL-27 alone can induce IL-10-producing Tr1 cells, but in the absence of TGF-β, the cells produce large quantities of both IFN-γ and IL-10. [18] IL-6 and IL-21 also plays a role in differentiation as they regulate expression of transcription factors necessary for IL-10 production, which is believed to start up the differentiation itself later on.
Proposed transcription biomarkers for type 1 regulatory cells differentiation are: [18]
Expression of these transcriptional factors are driven by IL-6 in IL-21 and IL-2 dependant manner.
Tr1 cells possess huge clinical potential in means to prevent, block and even cure several T cells mediated diseases, including GvHD, allograft rejection, autoimmunity and chronic inflammatory diseases. The first successful tests were performed on mouse models [19] [20] and on humans as well. [20] [21]
Transplantation research has shown, that donor Tr1 in response to recipient alloantigens, was found to correlate with the absence of GvHD after bone marrow transplantation, while decreased numbers of Tr1 markedly associated with severe GvHD. [21] Decreased levels of IL-10 CD4+ producing cells were also observed in inflamed synovium and peripheral blood of patients with rheumatoid arthritis. [7]
Phase I/II of clinical trials of Tr1 cell treatment concerning Crohn's disease have been successful and appear to be safe and do not lead to a general immune suppression. [20] [21]
T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.
Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
Alloimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigens and histocompatibility antigens. In alloimmunity, the body creates antibodies against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.
FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.
Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissues that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.
Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.
In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.
Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.
Follicular helper T cells (also known as follicular B helper T cells and abbreviated as TFH), are antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches, and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, TFH cells trigger the formation and maintenance of germinal centers through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate from T cell zones into these seeded germinal centers, predominantly composed of rapidly dividing B cells mutating their Ig genes. Within germinal centers, TFH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into long-lived plasma cells capable of producing high affinity antibodies against foreign antigen, or germinal center-dependent memory B cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered. TFH cells are also thought to facilitate negative selection of potentially autoimmune-causing mutated B cells in the germinal center. However, the biomechanisms by which TFH cells mediate germinal center tolerance are yet to be fully understood.
Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.
Regulatory macrophages (Mregs) represent a subset of anti-inflammatory macrophages. In general, macrophages are a very dynamic and plastic cell type and can be divided into two main groups: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2 group can further be divided into sub-groups M2a, M2b, M2c, and M2d. Typically the M2 cells have anti-inflammatory and regulatory properties and produce many different anti-inflammatory cytokines such as IL-4, IL-33, IL-10, IL-1RA, and TGF-β. M2 cells can also secrete angiogenic and chemotactic factors. These cells can be distinguished based on the different expression levels of various surface proteins and the secretion of different effector molecules.
Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases. It must provide absence of specific antibodies for exactly that antigenes.
Infectious tolerance is a term referring to a phenomenon where a tolerance-inducing state is transferred from one cell population to another. It can be induced in many ways; although it is often artificially induced, it is a natural in vivo process. A number of research deal with the development of a strategy utilizing this phenomenon in transplantation immunology. The goal is to achieve long-term tolerance of the transplant through short-term therapy.
In cell biology, TH9 cells are a sub-population of CD4+T cells that produce interleukin-9 (IL-9). They play a role in defense against helminth infections, in allergic responses, in autoimmunity, and tumor suppression.
Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.
B10 cells are a sub-class of regulatory B-cells that are involved in inhibiting immune responses in both humans and mice. B10 cells are named for their ability to produce inhibitory interleukin: Interleukin-10 (IL-10). One of their unique abilities is that they suppress the innate and adaptive immune signals, making them important for regulating the inflammatory response. Like the B cell, the B10 cell requires antigen specific binding to the surface of CD5 receptor to illicit a response from the T-cell. Once an antigen binds to the CD19 receptor, immediate downregulation in B-cell receptor (BCR) signal expression occurs and mediates the release of IL-10 cytokines. In mice and humans, B10 cells are distinguishable in their expression of measurable IL-10 due to the lack of unique cell surface markers expressed by regulatory B cells. However, IL-10 competence is not limited to any one subset of B cells. B10 cells do not possess unique phenotypic markers or transcription factors for further identification. B10 cells predominantly localize in the spleen, though they are also found in the blood, lymph nodes, Peyer's patches, intestinal tissues, central nervous system, and peritoneal cavity. B10 cells proliferate during inflammatory and disease responses.
Maria Grazia Roncarolo is an Italian pediatrician who is currently George D. Smith Professor in Stem Cell and Regenerative Medicine and Professor of Medicine at Stanford University. She is also the Director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine along with Irving Weissman and Michael Longaker and the Director for Center for Definitive and Curative Medicine at Stanford.